Sudden cardiac death accounts for 30-50% 0f heart failure mortality. This proposal, which is the continuation of an existing SCOR program in Sudden Cardiac Death, investigates the biological basis of altered excitability in heart failure and how predisposes to fatal ventricular arrhythmias. The SCOR is motivated by the following central hypothesis: Abnormalities of ionic currents and calcium handling render repolarization unstable in failing myocardium, increasing spatiotemporal variability of repolarization and predisposing patients with heart failure to sudden death. This hypothesis has been tested and validated extensively in the first five years of the program. We now propose to probe the biological basis of the abnormal repolarization, with a view to developing novel strategies for the identification of patients at high risk. Our program features a central animal model (pacing tachycardia canine heart failure) as well as tissue and myocytes from explanted human hearts. The program consists of five projects and five cores. Project 1, directed by Eduardo Marban, will use gene transfer and cell fusion to dissect the molecular determinants of cardiac repolarization. Project 2 focuses on L- type calcium channel inactivation. Project 2 focuses on L-type calcium channel inactivation under the leadership of David Yue. Project 3, directed by Gordon Tomaselli, investigates the relative roles of voltage- dependent and calcium-dependent mechanisms in the action potential prolongation of heart failure. Project 4 probes the neurohumoral modulation of electromechanical remodeling in heart failure, under the directorship of David Kass. Project 5, led by Ronald Berger, examines temporal QT interval variability as a predictor of severe arrhythmias and sudden cardiac death in patients. The five cores will provide support in the following areas: administrative matters, molecular genetics and vectors, animal models and cells, human cells and tissue, and quantitative modeling. The program in its first five years has been highly productive and interactive. The proposed continuation combines existing strengths with new approaches in a strongly synergistic manner.